Transmissible spongiform encephalopathies (TSE) are degenerative brain diseases that occur in primates and ruminants, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) and several human diseases such as Creutzfeldt-Jakob disease, Kuru, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Recent evidence indicates transmission of BSE across species barrier to humans resulting in a distinct Creutzfeldt-Jakob disease (vCJD). Although roughly only 130 cases of vCJD have occurred, several million persons including over 3 million Americans have been exposed to meat from contaminated BSE cows. The long incubation period of TSE disease suggests this may turn out to be a major health problem in the future. Prion protein (PrP) plays an essential role in TSE disease as the presence of both the normal PrP (PrPsen) and the abnormal prbtease resistant PrP (PrPres) is required for disease associated with TSE. This Program Project is designed to test the hypothesis that antibodies directed to PrP can both map the structure of the molecule and act to prevent the conversion of PrPsen to PrPres. These antibodies and small molecules that mimic their interaction with PrP may be useful both as diagnostic markers and therapies. Anthony Williamson who, with Dennis Burton, developed recombinant phage antibodies to PrP will continue to obtain and clone novel anti-PrP antibodies and use these reagents to study function-structure of PrP. Dennis Burton will focus primarily on study of PrP antibody-PrP interactions in order to develop small molecules that can pass the blood-brain-barrier. Michael Oldstone will continue to generate novel transgenic mouse models designed to analyze PrP turnover, role of GP1 anchor of PrP and use models that shorten the incubation time to develop TSE to test the efficiency of the antibodies and small mimicking molecules designed by Williamson and Burton, respectively. Lastly, Jose Criado will continue his electrophysiology and behavioral studies on the normal function of PrP and on its aberrations during TSE disease.